Metformin Suppresses Development of the Echinococcus multilocularis Larval Stage by Targeting the TOR Pathway.
Identifieur interne : 000085 ( Main/Exploration ); précédent : 000084; suivant : 000086Metformin Suppresses Development of the Echinococcus multilocularis Larval Stage by Targeting the TOR Pathway.
Auteurs : Julia A. Loos [Argentine] ; Valeria A. Dávila [Argentine] ; Klaus Brehm [Allemagne] ; Andrea C. Cumino [Oman, Argentine]Source :
- Antimicrobial agents and chemotherapy [ 1098-6596 ] ; 2020.
Abstract
Alveolar echinococcosis (AE) is a severe disease caused by the larval stage of the tapeworm Echinococcus multilocularis Current chemotherapeutic treatment options based on benzimidazoles are of limited effectiveness, which underlines the need to find new antiechinococcosis drugs. Metformin is an antihyperglycemic and antiproliferative agent that shows activity against the related parasite Echinococcus granulosus Hence, we assessed the in vitro and in vivo effects of the drug on E. multilocularis Metformin exerted significant dose-dependent killing effects on in vitro cultured parasite stem cells and protoscoleces and significantly reduced the dedifferentiation of protoscoleces into metacestodes. Likewise, oral administration of metformin (50 mg/kg of body weight/day for 8 weeks) was effective in achieving a significant reduction of parasite weight in a secondary murine AE model. Our results revealed mitochondrial membrane depolarization, activation of Em-AMPK, suppression of Em-TOR, and overexpression of Em-Atg8 in the germinal layer of metformin-treated metacestode vesicles. The opposite effects on the level of active Em-TOR in response to exogenous insulin and rapamycin suggest that Em-TOR is part of the parasite's insulin signaling pathway. Finally, the presence of the key lysosomal pathway components, through which metformin reportedly acts, was confirmed in the parasite by in silico assays. Taken together, these results introduce metformin as a promising candidate for AE treatment. Although our study highlights the importance of those direct mechanisms by which metformin reduces parasite viability, it does not necessarily preclude any additional systemic effects of the drug that might reduce parasite growth in vivo.
DOI: 10.1128/AAC.01808-19
PubMed: 32540980
PubMed Central: PMC7449199
Affiliations:
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Cumino</name><affiliation wicri:level="1"><nlm:affiliation>Laboratorio de Zoonosis Parasitarias, Departamento de Biología, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata (UNMdP), Mar del Plata, Argentina acumino@gmail.com.</nlm:affiliation><country wicri:rule="url">Oman</country><wicri:regionArea>Laboratorio de Zoonosis Parasitarias, Departamento de Biología, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata (UNMdP), Mar del Plata</wicri:regionArea><wicri:noRegion>Mar del Plata</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Mar del Plata, Argentina.</nlm:affiliation><country xml:lang="fr">Argentine</country><wicri:regionArea>Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Mar del Plata</wicri:regionArea><wicri:noRegion>Mar del Plata</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Departamento de Química, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata (UNMdP), Mar del Plata, Argentina.</nlm:affiliation><country xml:lang="fr">Argentine</country><wicri:regionArea>Departamento de Química, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata (UNMdP), Mar del Plata</wicri:regionArea><wicri:noRegion>Mar del Plata</wicri:noRegion></affiliation></author></analytic><series><title level="j">Antimicrobial agents and chemotherapy</title><idno type="eISSN">1098-6596</idno><imprint><date when="2020" type="published">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Alveolar echinococcosis (AE) is a severe disease caused by the larval stage of the tapeworm <i>Echinococcus multilocularis</i> Current chemotherapeutic treatment options based on benzimidazoles are of limited effectiveness, which underlines the need to find new antiechinococcosis drugs. Metformin is an antihyperglycemic and antiproliferative agent that shows activity against the related parasite <i>Echinococcus granulosus</i> Hence, we assessed the <i>in vitro</i> and <i>in vivo</i> effects of the drug on <i>E. multilocularis</i> Metformin exerted significant dose-dependent killing effects on <i>in vitro</i> cultured parasite stem cells and protoscoleces and significantly reduced the dedifferentiation of protoscoleces into metacestodes. Likewise, oral administration of metformin (50 mg/kg of body weight/day for 8 weeks) was effective in achieving a significant reduction of parasite weight in a secondary murine AE model. Our results revealed mitochondrial membrane depolarization, activation of Em-AMPK, suppression of Em-TOR, and overexpression of Em-Atg8 in the germinal layer of metformin-treated metacestode vesicles. The opposite effects on the level of active Em-TOR in response to exogenous insulin and rapamycin suggest that Em-TOR is part of the parasite's insulin signaling pathway. Finally, the presence of the key lysosomal pathway components, through which metformin reportedly acts, was confirmed in the parasite by <i>in silico</i> assays. Taken together, these results introduce metformin as a promising candidate for AE treatment. Although our study highlights the importance of those direct mechanisms by which metformin reduces parasite viability, it does not necessarily preclude any additional systemic effects of the drug that might reduce parasite growth <i>in vivo</i>.</div></front></TEI><pubmed><MedlineCitation Status="In-Process" Owner="NLM"><PMID Version="1">32540980</PMID><DateRevised><Year>2020</Year><Month>10</Month><Day>26</Day></DateRevised><Article PubModel="Electronic-Print"><Journal><ISSN IssnType="Electronic">1098-6596</ISSN><JournalIssue CitedMedium="Internet"><Volume>64</Volume><Issue>9</Issue><PubDate><Year>2020</Year><Month>08</Month><Day>20</Day></PubDate></JournalIssue><Title>Antimicrobial agents and chemotherapy</Title><ISOAbbreviation>Antimicrob Agents Chemother</ISOAbbreviation></Journal><ArticleTitle>Metformin Suppresses Development of the Echinococcus multilocularis Larval Stage by Targeting the TOR Pathway.</ArticleTitle><ELocationID EIdType="pii" ValidYN="Y">e01808-19</ELocationID><ELocationID EIdType="doi" ValidYN="Y">10.1128/AAC.01808-19</ELocationID><Abstract><AbstractText>Alveolar echinococcosis (AE) is a severe disease caused by the larval stage of the tapeworm <i>Echinococcus multilocularis</i> Current chemotherapeutic treatment options based on benzimidazoles are of limited effectiveness, which underlines the need to find new antiechinococcosis drugs. Metformin is an antihyperglycemic and antiproliferative agent that shows activity against the related parasite <i>Echinococcus granulosus</i> Hence, we assessed the <i>in vitro</i> and <i>in vivo</i> effects of the drug on <i>E. multilocularis</i> Metformin exerted significant dose-dependent killing effects on <i>in vitro</i> cultured parasite stem cells and protoscoleces and significantly reduced the dedifferentiation of protoscoleces into metacestodes. Likewise, oral administration of metformin (50 mg/kg of body weight/day for 8 weeks) was effective in achieving a significant reduction of parasite weight in a secondary murine AE model. Our results revealed mitochondrial membrane depolarization, activation of Em-AMPK, suppression of Em-TOR, and overexpression of Em-Atg8 in the germinal layer of metformin-treated metacestode vesicles. The opposite effects on the level of active Em-TOR in response to exogenous insulin and rapamycin suggest that Em-TOR is part of the parasite's insulin signaling pathway. Finally, the presence of the key lysosomal pathway components, through which metformin reportedly acts, was confirmed in the parasite by <i>in silico</i> assays. Taken together, these results introduce metformin as a promising candidate for AE treatment. Although our study highlights the importance of those direct mechanisms by which metformin reduces parasite viability, it does not necessarily preclude any additional systemic effects of the drug that might reduce parasite growth <i>in vivo</i>.</AbstractText><CopyrightInformation>Copyright © 2020 American Society for Microbiology.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y" EqualContrib="Y"><LastName>Loos</LastName><ForeName>Julia A</ForeName><Initials>JA</Initials><AffiliationInfo><Affiliation>Laboratorio de Zoonosis Parasitarias, Departamento de Biología, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata (UNMdP), Mar del Plata, Argentina.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Mar del Plata, Argentina.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y" EqualContrib="Y"><LastName>Dávila</LastName><ForeName>Valeria A</ForeName><Initials>VA</Initials><AffiliationInfo><Affiliation>Laboratorio de Zoonosis Parasitarias, Departamento de Biología, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata (UNMdP), Mar del Plata, Argentina.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Mar del Plata, Argentina.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Brehm</LastName><ForeName>Klaus</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>University of Würzburg, Institute of Hygiene and Microbiology, Würzburg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cumino</LastName><ForeName>Andrea C</ForeName><Initials>AC</Initials><AffiliationInfo><Affiliation>Laboratorio de Zoonosis Parasitarias, Departamento de Biología, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata (UNMdP), Mar del Plata, Argentina acumino@gmail.com.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Mar del Plata, Argentina.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Departamento de Química, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata (UNMdP), Mar del Plata, Argentina.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><Acronym>WT_</Acronym><Agency>Wellcome Trust</Agency><Country>United Kingdom</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2020</Year><Month>08</Month><Day>20</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Antimicrob Agents Chemother</MedlineTA><NlmUniqueID>0315061</NlmUniqueID><ISSNLinking>0066-4804</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="Y">Ragulator</Keyword><Keyword MajorTopicYN="Y">TOR</Keyword><Keyword MajorTopicYN="Y">alveolar echinococcosis</Keyword><Keyword MajorTopicYN="Y">metformin</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2019</Year><Month>09</Month><Day>03</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2020</Year><Month>06</Month><Day>08</Day></PubMedPubDate><PubMedPubDate PubStatus="pmc-release"><Year>2021</Year><Month>02</Month><Day>20</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2020</Year><Month>6</Month><Day>17</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2020</Year><Month>6</Month><Day>17</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate 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IdType="pubmed">19244117</ArticleId></ArticleIdList></Reference></ReferenceList></PubmedData></pubmed><affiliations><list><country><li>Allemagne</li><li>Argentine</li><li>Oman</li></country><region><li>Bavière</li><li>District de Basse-Franconie</li></region><settlement><li>Wurtzbourg</li></settlement></list><tree><country name="Argentine"><noRegion><name sortKey="Loos, Julia A" sort="Loos, Julia A" uniqKey="Loos J" first="Julia A" last="Loos">Julia A. Loos</name></noRegion><name sortKey="Cumino, Andrea C" sort="Cumino, Andrea C" uniqKey="Cumino A" first="Andrea C" last="Cumino">Andrea C. Cumino</name><name sortKey="Cumino, Andrea C" sort="Cumino, Andrea C" uniqKey="Cumino A" first="Andrea C" last="Cumino">Andrea C. Cumino</name><name sortKey="Davila, Valeria A" sort="Davila, Valeria A" uniqKey="Davila V" first="Valeria A" last="Dávila">Valeria A. Dávila</name><name sortKey="Davila, Valeria A" sort="Davila, Valeria A" uniqKey="Davila V" first="Valeria A" last="Dávila">Valeria A. Dávila</name><name sortKey="Loos, Julia A" sort="Loos, Julia A" uniqKey="Loos J" first="Julia A" last="Loos">Julia A. Loos</name></country><country name="Allemagne"><region name="Bavière"><name sortKey="Brehm, Klaus" sort="Brehm, Klaus" uniqKey="Brehm K" first="Klaus" last="Brehm">Klaus Brehm</name></region></country><country name="Oman"><noRegion><name sortKey="Cumino, Andrea C" sort="Cumino, Andrea C" uniqKey="Cumino A" first="Andrea C" last="Cumino">Andrea C. Cumino</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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